In recent years, successive cloning studies of the glutamate receptor gene have been conducted, with the finding that glutamate receptors have many subtypes. At present, glutamate receptors are generally divided into two categories: “ionotropic receptors having an ionic channel structure” and “metabotropic receptors coupled to G-protein”. Further, ionotropic glutamate receptors are divided into three groups: NMDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate receptors (Non-Patent Document 1), while metabotropic glutamate receptors are divided into eight groups, mGluR1 to mGluR8 (Non-Patent Documents 2 and 3). Group 2 metabotropic glutamate receptors exist in the presynapses of the glutamatergic nervous system and function as autoreceptors, thus suppressing excessive release of glutamic acid (Non-Patent Documents 4 and 5). Since the glutamatergic nervous system is involved in various neuropsychiatric functions, it is inferred that compounds acting on group 2 metabotropic glutamate receptors may be effective for treatment or prevention of acute and chronic neuropsychiatric diseases and neurological diseases.
As a group 2 metabotropic glutamate receptor agonist, (1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid is disclosed (Patent Document 1). The EC50 values for the agonistic activity are 29.4 nM and 45.4 nM for mGluR2 and mGluR3, respectively, and it has been confirmed that the agonist has the effect of suppressing phencyclidine-elicited hyperactivity in schizophrenia model rat, with a reported ED50 value of 5.1 mg/kg. It also has been confirmed that the agonist has the effect of suppressing phencyclidine-elicited head-weaving behavior and conditioned avoidance response, which are schizophrenia models (Non-Patent Documents 6 and 7).
However, the oral absorbability of (1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid is poor in monkeys. This suggests the possibility that the oral absorbability may also be poor in humans.
There are mainly two approaches to improvement of the mucosal absorbability (e.g., oral absorbability) of compounds. One is a method of changing their chemical structures themselves and the other is a method of devising a means of formulation without changing their chemical structures. The former method encompasses attaching a small modifying group such as an alkyl group or an acyl group to a reactive substituent such as a hydroxyl group or amino group of compounds to form them into prodrugs.
Compounds preferred as the aforementioned prodrugs are compounds that exist stably in prodrug forms before absorption, exhibit improved absorption after being formed into prodrugs and are converted to parent compound chemically or enzymatically and rapidly in the small intestine, the liver and/or plasma during and/or after absorption.
However, it is difficult to develop ideal prodrugs that satisfy all of the aforementioned conditions. For example, prodrug derivatives having an ester bond can be more likely to be hydrolyzed, which may have a great influence on chemical stability before absorption. As for prodrug derivatives having an amide bond, a great change of the physical properties of compounds may have a great influence on mucosal absorbability such as oral absorbability. Further, an amide bond is less likely to be hydrolyzed, which may have a great influence on biotransformation of compounds to parent compounds and plasma concentrations. Furthermore, it is difficult to predict the Pharmacokinetic profiles of prodrugs because enzymes that control biotransformation of prodrugs to parent compounds are substrate-specific and particularly, for example, the steric hindrance of a substituent inserted for formation of prodrugs prevents reaction of the enzymes. For these reasons, it is by no means easy to enhance the plasma concentrations of parent compounds by estimating possible improvements in the mucosal absorbability (e.g., oral absorbability) of prodrugs and their transformation to the parent compounds.
In fact, Patent Document 1 provides general descriptions on prodrugs of (1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, but no concrete disclosures on the prodrugs. There have been no successful examples of formation of prodrugs so far since 1999, when the application according to the patent document was filed.